PROJECT SUMMARY The ventral tegmental area (VTA) is a core component of the neural circuitry that drives goal-directed behavior, and a primary target through which drugs of abuse modulate behavior. Although generally regarded as a dopaminergic nucleus, about half of VTA neurons signal through release of the amino acid neurotransmitters GABA and glutamate. These neurons are also targets of drugs of abuse but much less studied. Recent evidence from our lab and others has begun to show that, like VTA DA neurons, activity in VTA GABA and glutamate neurons can profoundly shape motivated behaviors. Furthermore, sub-populations of VTA neurons release more than one of these three recycling transmitters, including neurons that co-release dopamine and glutamate, or glutamate and GABA. The goals of this proposal are to identify how transmitter co-release from VTA contributes to the processes underlying behavioral reinforcement, and how co-releasing neurons functionally integrate into the mesolimbic neural circuits that regulate motivated behavior. We will use an array of genetic approaches in combination with behavioral, anatomical, and electrophysiological assays in mice to selectively probe the connectivity and function of discrete VTA circuits. Together this continuing research program comprises a thorough plan to define the form and function of novel classes of VTA neurons and enhance our understanding of how intrinsic VTA heterogeneity shapes behaviors relevant to neuropsychiatric disease.